Amyloid-beta (Abeta) is a 39-43 amino acid peptide derived from a large precursor protein known as the amyloid precursor protein (APP). Abundant evidence suggests that the conversion of Abeta from soluble to insoluble forms and its buildup in the brain is a key step in the pathogenesis of Alzheimer's disease (AD). There is a strong likelihood that prevention/reversal of this process may serve as a treatment for AD. Utilization of transgenic (Tg) mouse models of AD which develop age-dependent Abeta deposition have provided useful models to test whether different manipulations can influence this and other AD-related pathology. Recent studies have shown that active immunization in Tg mouse models of AD can decrease Abeta deposition and that passive parenteral administration of certain anti-Abeta antibodies appear to mimic this effect. The mechanism as to how anti-Abeta antibodies result in prevention/reversal of Abeta deposition has not yet been clarified. In exploring factors which alter soluble Abeta clearance, we found that a monoclonal antibody (m266) directed against the central domain of Abeta was able to bind and completely sequester all plasma Abeta in a mouse model of APPV717F Tg mice. Peripheral administration of m266 to APPV717F Tg mice, in which Abeta is generated specifically within the CNS, resulted in a rapid 1000-fold increase in plasma Abeta and altered dynamics of extracellular Abeta metabolism in the CNS. Peripheral administration of m266 to APPV717F Tg mice also markedly reduced Abeta deposition in the brain when administered chronically. Thus, our findings have led us to hypothesize that certain anti-Abeta antibodies alter Abeta clearance and diminish AD pathology in large part by increasing net transport of Abeta from CNS to plasma. We will test this and other ideas in the following Aims: Aim 1: We have developed an in vivo assay to measure the net rate of Abeta entering the plasma of APPV717F Tg mice. Utilizing this assay, we will test the hypothesis that the ability of specific anti-Abeta antibodies to result in net "efflux" of Abeta from CNS to plasma will best correlate with their ability to prevent/reverse Abeta deposition chronically. Aim 2: Our preliminary data suggest that the rate of Abeta entry from CNS to plasma is influenced by the presence or absence of Abeta deposits in plaques. We will test this idea in APP V717F 00Tg mice with our in vivo Abeta efflux assay. Aim 3: Abeta is transported from CNS to plasma and plasma to CNS across the blood brain barrier. We will use direct methods to determine the effect of anti-Abeta antibodies on bi-directional transport rates of Abeta from brain to plasma and from plasma to brain. This will determine how anti-Abeta antibodies influence CNS/plasma Abeta transport exchanges.